The unifying hypothesis of this proposal is that the use of biomaterial scaffolds is critical to the development of successful therapies for spinal cord injury. In the absence of a biomaterial scaffold that can help to bridge the injury site, the lack of regeneration promoting substrates in the injured spinal cord limits the efficacy of growth factor delivery and cell transplantation approaches. We hypothesize that controlled release of growth factors over a prolonged period of time (weeks) from a fibrin-based biomaterial scaffold alone or in combination with embryonic stem cell-derived neural lineage cells (ESNLCs) is needed to achieve significant regeneration following spinal cord injury. This hypothesis will be tested systematically by addressing the following specific aims, all of which are necessary to achieve the goal of spinal cord regeneration. The aims of this proposal are: (1) To test the hypothesis that a fibrin-based biomaterial scaffold enables sufficient controlled release of growth factor (neurotrophin-3) to enable enhanced short and long-term regeneration compared to uncontrolled growth factor release in a rat spinal cord injury model. (2) To test the hypothesis that growth factor delivery from a fibrin-based biomaterial scaffold will enable survival and differentiation of embryonic stem cell-derived neural lineage cells (ESNLCs) into neurons in an in vitro setting comparable to or better than that observed with traditional differentiation protocols. (3) To test the hypothesis that growth factor delivery from a fibrin-based biomaterial scaffold will enable enhance survival and differentiation of embryonic stem cell-derived neural lineage cells (ESNLCs) into neurons compared with ESNLCs alone (no scaffold) in vivo in the setting of spinal cord injury.